The present invention relates to novel large-ring diamine platinum(II) and platinum(IV) complexes useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to a pharmaceutical method of treatment. More particularly, the novel complexes of the present invention are active against the L1210 murine leukemia cell lines, thus inhibiting the growth of malignant neoplasms in mammals.
Various platinum compounds have been shown to possess antitumor activity. This has been highlighted by the clinical utility of cisplatin (A) ##STR1## in the treatment of human tumors. However, because of the severe toxicity, especially nephrotoxicity, associated with the therapeutic use of cisplatin, a number of additional platinum(II) and platinum(IV) analogs have been synthesized and evaluated for antitumor activity. Thus, U.S. Pat. No. 4,477,387 (hereinafter the '387 patent) discloses "platinum(II) complexes represented by the general formula: ##STR2## wherein --B--B-- is ##STR3## (in which R.sub.1 and R.sub.2 are the same or different and each is hydrogen, an alkyl group or an aryl group, and n, m and l are 0 or is an integer of from 1 to 3), at least one of A.sub.1 and A.sub.2 is ##STR4## (hereinafter referred to as a ligant of D-gluconic acid) and the other is the ligand of D-gluconic acid, Cl.sup.-, Br.sup.-, I.sup.-, F.sup.-, XCH.sub.2 COO.sup.- (in which X is a halogen atom), NO.sub.3.sup.-, SO.sub.4.sup.--, H.sub.2 PO.sub.4.sup.- or H.sub.2 O or, when taken together, A.sub.1 and A.sub.2 may form a ring together with Pt(II), in the latter case --A.sub.1 --A.sub.2 -- being the ligand of D-gluconic acid" which have antineoplastic activity.
European Patent Application 0 282,672 (hereinafter the '672 patent application) discloses platinum(II) complexes having antitumor effects and are represented by the formula: ##STR5## wherein R.sub.1 and R.sub.2 are each a lower alkyl group; and the two X's are each a halogen atom or jointly form a group represented by ##STR6## wherein R.sub.3 and R.sub.4 are each a hydrogen atom or a lower alkyl group; or a group represented by ##STR7## wherein m is 1 or 2.
However, the previous complexes of platinum(II) do not disclose nor suggest the complexes of the present invention. Thus, the '387 patent discloses complexes in which the diamine ligand may be a five to an eleven membered ring. However, rings greater than six members were not exemplified and not characterized by analysis or biological test results. Additionally, all the platinum(II) complexes of the '387 patent contained at least one D-gluconic acid ligand. The '672 patent application discloses only seven membered ring complexes. Thus, we have found unexpectedly that platinum(II) and platinum(IV) complexes in which the diamine ligand is an eight to twelve membered ring have antineoplastic activity.